PMID:22837859

Citation	Muñoz, NM, Desai, A, Meliton, LN, Meliton, AY, Zhou, T, Leff, AR and Dudek, SM (2012) Group V phospholipase A(2) increases pulmonary endothelial permeability through direct hydrolysis of the cell membrane. Pulm Circ 2:182-92
Abstract	Acute lung injury (ALI) is characterized by inflammatory disruption of the alveolar-vascular barrier, resulting in severe respiratory compromise. Inhibition of the intercellular messenger protein, Group V phospholipase A(2) (gVPLA(2)), blocks vascular permeability caused by LPS both in vivo and in vitro. In this investigation we studied the mechanism by which recombinant gVPLA(2) increases permeability of cultured human pulmonary endothelial cells (EC). Exogenous gVPLA(2) (500 nM), a highly hydrolytic enzyme, caused a significant increase in EC permeability that began within minutes and persisted for >10 hours. However, the major hydrolysis products of gVPLA(2) (Lyso-PC, Lyso-PG, LPA, arachidonic acid) did not cause EC structural rearrangement or loss of barrier function at concentrations <10 μM. Higher concentrations (≥ 30 μM) of these membrane hydrolysis products caused some increased permeability but were associated with EC toxicity (measured by propidium iodide incorporation) that did not occur with barrier disruption by gVPLA(2) (500 nM). Pharmacologic inhibition of multiple intracellular signaling pathways induced by gVPLA(2) activity (ERK, p38, PI3K, cytosolic gIVPLA(2)) also did not prevent EC barrier disruption by gVPLA(2). Finally, pretreatment with heparinase to prevent internalization of gVPLA(2) did not inhibit EC barrier disruption by gVPLA(2). Our data thus indicate that gVPLA(2) increases pulmonary EC permeability directly through action as a membrane hydrolytic agent. Disruption of EC barrier function does not depend upon membrane hydrolysis products, gVPLA(2) internalization, or upregulation of downstream intracellular signaling.
Links	PubMed PMC3401872 Online version:10.4103/2045-8932.97604
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PA2GA		GO:0070374: positive regulation of ERK1 and ERK2 cascade	ECO:0000314:		P		Figure 6 shows that Group V phospholipase A2 activity has an effect on human pulmonary endothelial cells' intracellular signaling.	complete CACAO 5637
HUMAN:PA2GA		GO:0010518: positive regulation of phospholipase activity	ECO:0000314:		P		Figure 6 shows that Group V phospholipase A2 activity has an effect on human pulmonary endothelial cells' intracellular signaling.	complete
HUMAN:PA2GA	involved_in	GO:0070374: positive regulation of ERK1 and ERK2 cascade	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PA2G5		GO:0070374: positive regulation of ERK1 and ERK2 cascade	ECO:0000314:		P		Figure 6 shows that Group 5 phospholipase A2 (gVPLA2) "stimulates upregulation of multiple downstream signaling cascades," which includes the ERK 1 and 2 cascades.	complete CACAO 5802
HUMAN:PA2G5		GO:0010518: positive regulation of phospholipase activity	ECO:0000314:		P		Figure 6 shows that activation of group 5 phospholipase A2 positively regulates phospholipase activity.	complete CACAO 5806
HUMAN:PA2G5	involved_in	GO:0070374: positive regulation of ERK1 and ERK2 cascade	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PA2G5	involved_in	GO:0010518: positive regulation of phospholipase activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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